Vanadyl sulfate (VOSO.sub.4), which is readily available over the counter in the United States at local health food stores, is marketed as a nutritional supplement. Although it is used for other purposes as well, vanadyl sulfate has been taken to improve glycemic control. Vanadyl sulfate generates the vanadyl radical (VO.sup.-3) which has been shown to reverse diabetes in pancreatectomized rats. The radical (VO.sub.3.sup.-) is the predominate radical form in extracellular fluid. It is reduced intracellularly into the radical (VO.sup.+2) which is the active form.
During the past ten years there has been numerous publications in the medical scientific literature demonstrating that vanadyl radical generating compounds have exceptional antidiabetic effects in animals. Vanadyl sulfate orally administered to animals has been shown to produce normoglicemia which can persist even after discontinuation of the therapy.
Efforts to reproduce the antidiabetic effect in humans have been unsuccessful. Recent published human trials show only a mild improvement in glycemic control with administration of vanadyl sulfate.
Three factors appear to hinder the efficacy of vanadyl radical generating compounds in humans. First, only small amounts (0.1-2%) of the orally administered compounds are absorbed from the human gastrointestinal tract. Most of the compound is excreted in the urine.
Another limiting factor is that vanadyl radical generating compounds exhibit limited cytoplasmic penetration. The active component of vanadyl radical generating compounds (VO.sup.+2) is present in only very small concentrations in the intracellular compartment.
A third factor involves toxicity. Compounds which tend to have greater cellular penetration typically exhibit greater toxicity levels. In particular, vanadyl sulfate (VOSO.sub.4) is 1/10 as toxic than other vanadyl radical generating compounds. However, this compound has a lower antidiabetic potency than other vanadyl radical generating compounds probably due to lower cytoplasmic penetration. (VO.sup.+2) is found in the intracellular compartment after reduction from (VO.sub.3.sup.-) commonly present in the extracellular compartment. The VO.sup.+2 radical binds to sites located in the intracellular membrane surface inhibiting (Na.sup.+ +K.sup.+)--ATPase enzyme and thereby inhibiting the (K.sup.+) potassium pump. This occurs in all tissues of the body.
Sulfonylureas exert hypoglycemic action and inhibit potassium channel transport by binding to proteins at the potassium channel. Of the compounds commonly known as sulfonylureas, glyburide is considered the most potent because it binds most firmly and for a longer time to the 140 kda protein at the potassium channel of all tissues of the body. Micronized glyburide or small particle glyburide is absorbed more rapidly from the gastrointestinal tract than non-micronized glyburide.
Oral hypoglycemic agents such as tolazamide, tolbutamide, chlorpropamide, micronized and non-micronized glyburide, glimepiride, glypizide, metformin, and phenformin have been available as oral treatments for diabetes, typically non-insulin dependent (Type II) diabetes. Oral hypoglycemic agents in general are disadvantageous because the extent , predictability and duration of the antidiabetic effect is unpredictable and these agents are often characterized by primary or secondary failure. Because oral hypoglycemic agents exhibit inconsistent hypoglycemic benefit, insulin therapy is preferred.
For those diabetics in which current oral medication does not offer sufficient control of their condition, insulin injections are necessary. Daily injections offer a number of risks, including hypoglycemia, wide fluctuations in glucose concentrations requiring multiple daily serum glucose determinations and multiple insulin injections, and strict dietary control which then leads to the issue of poor compliance. Other disadvantages include difficulty in self administration of an accurate dose, especially by the elderly or infirmed patients. Epidemiological data shows that over 85% of insulin treated diabetics in the United States are poorly controlled. As a result, 150 billion dollars per year is spent treating the devastating complications of the illness.
Some patients are virtually impossible to treat with insulin because their cells cannot effectively utilize or are resistant to insulin therapy. As a result of the lack of glycemic control, diabetic patients often experience a variety of conditions including: neuropathy, nephropathy, cardiomyopathy, fetinopathy, coronary and peripherovascular disease and the like. These complications occur due to the unachieved glycemic control that results from failure of the insulin, diet and/or exercise only approach.
It would therefore be a significant advance in the art of treating diabetes to provide a composition which can effectively treat both Type I and Type II diabetes and which can provide effective glycemic control for all, including patients who cannot effectively utilize or are resistant to insulin therapy or who cannot achieve desired control of serum glucose levels with an insulin, diet and/or exercise approach. It would be a further advance in the art to provide such a composition in oral dosage form to ease the burden on patients who have been subjected to daily insulin injections and monitoring.